Immunotherapy includes a number of strategies that harness the immune system to help treat disease. Immunotherapy for cancer, as we know it, now relies on the activation of specific immune system cells known as T cells. Cancer drugs called immune checkpoint inhibitors act by removing the brakes imposed on T cells by tumors or by the body’s natural mechanisms for limiting their activation to prevent autoimmune disease.

In recent years, the U.S. Food and Drug Administration (FDA) has approved several immune checkpoint drugs for the treatment of various cancers. These drugs target proteins involved in activating the T cell response: PD-1, PD-L1, and CTLA4. Many clinical trials are testing drugs that target other immune checkpoint proteins (OX40, B7-H3, and LAG3, to name just a few), but no notable successes have been reported so far.

Now, some clinical investigators have turned their attention to a different arm of the immune system that could help treat cancer.

Harnessing an Ancient Immune Response

T cells are major players in the adaptive immune system—an arm of the immune system that “adapts” or educates itself to recognize highly specific targets (like mutant proteins in cancer cells or specific molecules found on viruses or other pathogens). This adaptive response takes a while to mount. Meanwhile, a more ancient arm of the immune system, the innate immune response, is not very specific, but provides very fast recognition of many kinds of pathogens, including viruses, bacteria, and parasites.

What has become clear is that the innate response also plays an integral role in the development of the adaptive response. The innate response involves cells (macrophages and dendritic cells) that may eventually present specific “foreign” molecules to T cells and initiate a specific, adaptive, response. When it comes to cancer, the problem is that the adaptive immune response is just not activated in in many patients. The reasons for this may be diverse, but in general, tumors that manage to dispel the adaptive immune response are known as immunologically “cold.”

In a new approach to cancer, scientists have hypothesized that a treatment strategy that activates the innate response could turn at least some immunologically “cold” tumors into “hot” ones. The innate immune response could be induced by mimicking an infection with foreign pathogens without actually introducing an infection.

Taking a “Toll” on Cancer

The key to this new treatment approach may be proteins known as toll-like receptors (TLRs), of which there are 10 different types. TLRs are found on the surface of macrophages—immune system cells that not only destroy incoming pathogens, but also may alert the adaptive immune system to an infection. Activation of TLRs occurs in response to sub-components of various invaders, but these components are often of a rather generic nature; they typically include certain types of bacterial or viral proteins, or simply nucleic acids (such as DNA or RNA). For example, a TLR known as TLR9 recognizes a motif in DNA sequences known as CpG, which is found far more frequently in bacterial than in our own DNA. In a healthy cell, DNA is found in in the nucleus and mitochondria, but a cell infected by a virus or intracellular bacteria will have the pathogen’s DNA in its cytosol (the liquid in a cell), inducing an innate immune response.

When a TLR9 “agonist,” such as a DNA molecule enriched in CpG , is injected into a tumor, this may trigger rapid activation of macrophages and dendritic cells (DCs) that express TLR9. The macrophages may directly destroy the infected cells, but, together with DCs, they may be able to alert T cells residing in the tumor or draining lymph nodes, and thus promote an adaptive immune response.

Indeed, earlier this year, a publication from Stanford scientist Ronald Levy, MD, showed stunning activity of CpG when combined with an anti-OX40 immune checkpoint drug in mice representing various human cancers. This work created a lot of excitement.

Even before that publication, TLR9 agonists very similar to CpG were in clinical trials. Excellent results have been reported for a CpG-type molecule known as SD-101 in slow-growing (indolent) lymphomas. In a clinical trial, 29 patients received low-dose irradiation and injections of SD-101 directly into their tumors (intratumoral injections). All patients experienced reduction in the size of the injected tumor, and most (24 patients) also experienced shrinking of other un-injected tumors.

A small trial showed really good results for patients with metastatic melanoma. Out of nine patients, eight (78%) had a durable response to SD-101 combined with intravenous delivery of the anti-PD-1 immune checkpoint drug pembrolizumab (Keytruda). Unfortunately, of 13 additional patients who had already been treated with anti-PD-1 drugs, only two have responded to the combination of SD-101 and pembrolizumab.

Another TLR9 agonist, IMO-2125, was also tested in metastatic melanoma, with the addition of intravenous ipilimumab (Yervoy), an anti-CTLA4 immune checkpoint drug. In this trial, 15 patients received intratumoral injections of IMO-2125 and ipilimumab. The researchers reported last June that 47% of the patients had significant reduction of tumor burden, and the overall disease control rate was 67%. Two patients had a complete response. Some of the patients had been treated with anti-PD-1 drugs prior to entry in this trial.

The following TLR9 agonists are in trials, mostly in combination with immune checkpoint drugs: SD-101, IMO-2125, MGN1703 (Lefitolimod), and DV281. Other TLR agonists are also in trials, particularly activators of TLR7/8, including NKTR-262 and MEDI9197.

The Potential of STING Agonists

The other key player in the body’s innate immune response is known as the stimulator of interferon genes (STING) pathway. The STING pathway was first discovered as a response to viral infections; it senses viral DNA in the cytosol of infected cells. As the name reflects, activation of the protein interferon, a very potent immune system stimulator, is a hallmark of this pathway, which could also play a role in cancer treatment.

In the STING pathway, a specific protein called cGAS recognizes DNA in the cytosol of an infected cell. cGAS produces a molecule called cGAMP, which activates the protein STING, for which the entire pathway is named. STING activates dendritic cells, which in turn may lead to the activation of the adaptive immune response involving T cells. There is evidence that the STING pathway may be involved in the efficacy of radiation as cancer treatment; the nuclei of cancer cells may break down during radiation, releasing DNA and activating the STING pathway.

Drugs that activate STING, or STING “agonists,” are now in clinical trials. These are either in a ring-shaped molecular structure known as a cyclic dinucleotide (like cGAMP) or some engineered agonist molecules that have been shown to activate production of interferon.

One has to be careful with these new drugs because systemic activation of interferon may cause strong inflammatory and autoimmune responses. Stimulation of STING should be transient, not chronic, and use of STING agonists is limited to intratumoral injections, similar to TLR9, in order to avoid potentially severe systemic effects. The STING agonists currently being tested in trials are ADU-S100/MIW815 and MK-1454, but additional molecules are advancing toward clinical development.

Drugs that activate the immune system to attack cancer in a process known as immune checkpoint blockade (ICB) are a focus of intense investigation. A number of them are already approved by the U.S. Food and Drug Administration (FDA) for various cancers; namely, the anti-CTLA4 antibody ipilimumab (Yervoy), two anti-PD-1 antibodies: pembrolizumab (Keytruda) and nivolumab (Opdivo), and three anti-PD-L1 drugs: atezolizumab (Tecentriq), avelumab (Bavencio) and durvalumab (Imfinzi). These ICB drugs have the potential to induce durable cancer regressions, but the majority of cancer patients just do not respond to them at all.

Biomarkers, signature molecules in the blood or other tissue, can sometimes be used to predict a patient’s response to a given treatment. But no reliable biomarkers exist for ICB, and this is a serious concern. Patients who may really benefit from ICB could be overlooked, and patients who are not likely to respond may receive useless (and very expensive) ICB treatment.

Most potential response predictors that have already been identified are not yet useful for one or all of the following reasons: they are not extensively validated, their significance is still uncertain and may differ from one cancer (or even one patient) to another, or they are technically challenging for routine use. These markers are addressed below. Continue reading…

This post is written by ASK Cancer Commons Scientist and Product Team Member Amanda Nottke, PhD. Dr. Nottke regularly provides guidance to patients through our ASK Cancer Commons service.

After a diagnosis of early stage, hormone-positive breast cancer, you may find yourself facing several daunting decisions, such as choosing between the extensive surgery of mastectomy versus a more minor lumpectomy procedure paired with radiation (with all its challenging side effects). And once surgery is complete, what next? Hormone therapy is clearly indicated for many women, but which drug, and how long to take it? And what about chemo—how to know if the tough side effects are worth the possible reduction in risk of recurrence?

Fortunately, there are a wealth of quality datasets available to inform these decisions. Below are some of the questions we get most frequently from patients using our ASK Cancer Commons service, answered according to the latest thinking from scientific literature and our expert physician network. If you are facing your own cancer treatment decisions and would like free one-one-one expert support, please submit your case here.

1. If my doctor has said either mastectomy or lumpectomy plus radiation are appropriate for me, how do I choose?

Many studies have looked at this, and overall the outcomes for mastectomy versus lumpectomy plus radiation are extremely similar (both are effective treatments, so you can instead weigh the side effects of radiation versus the more intensive surgery of the mastectomy). This webpage provides a helpful summary of the pros and cons of mastectomy compared to lumpectomy.Continue reading…

The human gut contains hundreds of species bacteria, which are known to contribute to various bodily functions (such as digestion, of course!) but they also shape our immune system. Now, recent research has revealed how our microbiomes (the abundant bacteria living in our bodies) may affect the efficacy of immune checkpoint blockade (ICB) in cancer treatment.

How it started: about two years ago, an American group of scientists led by Thomas Gajewski of the University of Chicago noticed that melanoma (and some other cancers’) growth in mice was influenced heavily by the type of bacteria found in the mouse gut. They worked with mice purchased from two different vendors, and realized that mice from one vendor had consistently slower-growing tumors. Bifidobacterium bacteria present in the mouse gut were pinpointed to be the culprit, because transfer of Bifidobacterium to mice that did not have it was able to slow down melanoma growth. Treatment with an immune anti-PD-L1 drug was effective in mice that had the bacteria, but not in mice lacking it. Continue reading…

Non-metastatic breast cancers are most often treated with surgery, but if the tumors are fairly large, or involve nearby lymph nodes, neoadjuvant (pre-operative) treatments with chemotherapy (NAC) are done first. NAC often reduces the tumor size and kills cancer cells in lymph nodes, if present, prior to surgery, improving the outcome. The best possible result of neoadjuvant treatment is pCR (pathologic compete response), when the tumor is no longer visible in imaging studies. Here, I review the new directions in which neoadjuvant treatments are evolving.

Today, treatments for metastatic breast cancers are tailored for specific subtypes. Starting with the introduction of the drug trastuzumab (Herceptin) for HER2-positive cancers, new, more specific treatment options were eventually developed and approved for other types as well. Estrogen deprivation endocrine therapies, lately prescribed in combination with CDK4/6 inhibitors, are used in estrogen receptor (ER)-positive cancers. Triple negative cancers (TNBC) are still treated mostly with chemotherapy, but immune checkpoint drugs and PARP inhibitors are explored in clinical trials, with some successes reported.

However, neoadjuvant treatments (except for HER2+ cancers) remain largely limited to chemotherapy regimens. This is starting to change now, with new approaches tailored to the cancer type being investigated in clinical trials.

In this regard, it is important to mention the I-SPY2 trial, NCT01042379, which started in 2010 and is for women with stage II-III breast cancer. It offers about a dozen drugs that are chosen based on particular features of the newly diagnosed cancers. This trial has a unique design and has produced some important results. Additional treatments and trials for various types of breast cancer are discussed below. Continue reading…

Last month, the annual American Society of Clinical Oncology (ASCO) meeting took place in Chicago. Thousands of oncologists, patients, and journalists gathered to learn about the most recent developments in cancer research and treatment. Here are some breast cancer highlights from the meeting:

Triple negative breast cancer (TNBC) is considered more responsive to treatment with immune checkpoint drugs than any other type of breast cancer. So far, these drugs have primarily been explored in metastatic TNBC, in combination with chemotherapy. The combination of “anti-PD-L1” and “anti-PD-1” immune checkpoint drugs with chemotherapy has now been examined in early-stage TNBC, in which a breast tumor can be surgically removed after neoadjuvant chemotherapy. Continue reading…

Liquid biopsies, virtually unknown even a year or two ago, are becoming common tools in precision diagnostics for cancer. Here, I will try to explain some of the more important differences between liquid and “traditional” tumor biopsies.

Biopsies of solid tumors (e.g., lung, breast, or brain tumors) involve surgically removing a small part of a tumor and sending it to pathology lab. In the last few years, doctors have also started to send some tumor samples to special service labs that analyze tumor DNA for the presence of cancer-related mutations.

By definition, regular biopsies can be intrusive and are sometimes associated with side effects, such as bleeding or infection. However, they provide some really essential information; i.e., the histology and grade of the tumor and other tumor characteristics necessary to determine the best choice of treatment. For lung cancer, for example, a biopsy determines the type of tumor—adenocarcinoma, squamous cancer, small-cell lung cancer, or another, less common type. For breast cancer, a routine test will determine if the tumor expresses estrogen, progesterone receptors, and a protein called HER2. These tests are critically important in guiding treatment choices. If mutational analysis of cancer-related genes is also performed (which doesn’t always happen, unfortunately), it may guide treatment with targeted drugs. Continue reading…

Terry Arnold has always identified as an advocate. “It’s my way,” she says. When she was younger, she helped establish the first rape crisis program in Fort Bend County, Texas. She is also a founding member of a center that works on missing children’s cases, often partnering with FBI task forces.

“I always joke that I was doing it all with a baby on my hip,” says Terry, who raised five children with her husband.

So it is no surprise that being diagnosed with inflammatory breast cancer (IBC), a rare and deadly disease, propelled Terry into her next chapter of advocacy work. “I was actually misdiagnosed for four months,” Terry says. “I was very fortunate to be alive at all.”

Her treatment regimen, which lasted from 2007 to 2008, was brutal but ultimately successful. Soon, her phone rang frequently with calls from other women with IBC who wanted her advice. Meanwhile, she became increasingly aware of the lack of adequate IBC education for both doctors and patients, as well as the lack of funding for IBC research.

“I hadn’t been that long out of treatment when I had gone to four funerals in six weeks, and not one of the girls was over 40, all with IBC,” Terry says. “I couldn’t take it. I reached out to organizations, but nobody wanted to talk about IBC. They’d say, ‘It’s too rare, they all die, there’s no early detection, what do you want us to do?’ ” Continue reading…

Doctors prescribe drugs known as CDK inhibitors to treat some women with estrogen-receptor-positive (ER+) metastatic breast cancer. Research into these drugs is ongoing, and new, promising CDK inhibitor options are on the horizon. Here, I address the current outlook for CDK inhibitors in ER+ breast cancer.

First, some background: ER+ breast cancers comprise about 70% of all breast cancers. The name reflects the fact that cells of these cancers express estrogen receptors (ERs), which are protein features targeted by many treatment strategies for this cancer type. The estrogen receptor (ER) protein is a treatment target not only because “it is there,” but mainly because it drives tumor cell proliferation in ER+ breast cancer. The activity of the ER depends on its binding to the hormone estrogen, and treatments known as endocrine drugs aim to prevent this interaction. Some endocrine drugs inhibit the synthesis of estrogen in the body (e.g., aromatase inhibitors, such as letrozole and anastrozole), and others prevent the interaction of estrogen with ERs (e.g., ER modulators such as tamoxifen, or the pure anti-estrogen drug fulvestrant). The problem of course is that, in metastatic breast cancer, resistance develops to each and every endocrine drug used. Continue reading…